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https://www.readbyqxmd.com/read/28931550/variation-in-akt-protein-kinases-in-human-populations
#1
Peter Rotwein
The three AKT kinases are related proteins that are essential for normal growth and metabolic regulation, and are implicated as key signaling mediators in many physiological and patho-physiological processes. Each AKT is activated by common biochemical signals that act downstream of growth factor and hormone receptors via phosphatidylinositol-3 kinase, and each controls several downstream pathways. The importance of AKT actions in human physiology is strengthened by the rarity of modifying mutations in their genes, and by the devastating impact caused by these mutations on growth and development, and in disorders such as cancer...
September 20, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/28928752/climate-clever-clovers-new-paradigm-to-reduce-the-environmental-footprint-of-ruminants-by-breeding-low-methanogenic-forages-utilizing-haplotype-variation
#2
Parwinder Kaur, Rudi Appels, Philipp E Bayer, Gabriel Keeble-Gagnere, Jiankang Wang, Hideki Hirakawa, Kenta Shirasawa, Philip Vercoe, Katia Stefanova, Zoey Durmic, Phillip Nichols, Clinton Revell, Sachiko N Isobe, David Edwards, William Erskine
Mitigating methane production by ruminants is a significant challenge to global livestock production. This research offers a new paradigm to reduce methane emissions from ruminants by breeding climate-clever clovers. We demonstrate wide genetic diversity for the trait methanogenic potential in Australia's key pasture legume, subterranean clover (Trifolium subterraneum L.). In a bi-parental population the broadsense heritability in methanogenic potential was moderate (H(2) = 0.4) and allelic variation in a region of Chr 8 accounted for 7...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28918591/platform-model-describing-pharmacokinetic-properties-of-vc-mmae-antibody-drug-conjugates
#3
Matts Kågedal, Leonid Gibiansky, Jian Xu, Xin Wang, Divya Samineni, Shang-Chiung Chen, Dan Lu, Priya Agarwal, Bei Wang, Ola Saad, Neelima Koppada, Bernard M Fine, Jin Y Jin, Sandhya Girish, Chunze Li
Antibody-drug conjugates (ADCs) developed using the valine-citrulline-MMAE (vc-MMAE) platform, consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile vc linker. Recently, clinical data for a variety of vc-MMAE ADCs has become available. The goal of this analysis was to develop a platform model that simultaneously described antibody-conjugated MMAE (acMMAE) pharmacokinetic (PK) data from eight vc-MMAE ADCs, against different targets and tumor indications; and to assess differences and similarities of model parameters and model predictions, between different compounds...
September 16, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28916300/distinct-neuronal-populations-in-the-basolateral-and-central-amygdala-are-activated-with-acute-pain-conditioned-fear-and-fear-conditioned-analgesia
#4
Ryan K Butler, Sarah Ehling, Megan Barbar, Jess Thomas, Mary A Hughes, Charles E Smith, Vladimir M Pogorelov, Dipendra K Aryal, William C Wetsel, B Duncan X Lascelles
Fear-conditioned analgesia (FCA) is modulated by brain areas involved in the descending inhibitory pain pathway such as the basolateral (BLA) and central amygdala (CEA). The BLA contains Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and parvalbumin (PV) neurons. CEA neurons are primarily inhibitory (GABAergic) that comprise enkephalin (ENK) interneurons and corticotropin-releasing factor (CRF) - neurons that project to the periaqueductal grey. The purpose of our experiment was to determine the pattern of activation of CaMKII/PV and ENK/CRF neurons following the expression of acute pain, conditioned fear, and FCA...
September 12, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28914978/model-informed-dose-optimization-of-dichloroacetate-for-the-treatment-of-congenital-lactic-acidosis-in-children
#5
Naveen Mangal, Margaret O James, Peter W Stacpoole, Stephan Schmidt
Dichloroacetate (DCA) is an investigational drug used to treat congenital lactic acidosis and other mitochondrial disorders. Response to DCA therapy in young children may be suboptimal following body weight-based dosing. This is because of autoinhibition of its metabolism, age-dependent changes in pharmacokinetics, and polymorphisms in glutathione transferase zeta 1 (GSTZ1), its primary metabolizing enzyme. Our objective was to predict optimal DCA doses for the treatment of congenital lactic acidosis in children...
September 15, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28910514/pharmacokinetics-of-single-dose-ceftaroline-fosamil-in-children-with-cystic-fibrosis
#6
Jennifer Le, John S Bradley, Sara Hingtgen, Shannon Skochko, Nanette Black, Ronald N Jones, Meerana Lim, Edmund V Capparelli
BACKGROUND: Single-dose pharmacokinetics (PK) and safety of ceftaroline fosamil with population pharmacokinetic/pharmacodynamic (PK/PD) modeling for staphylococcal pneumonia was performed in children with CF. METHODS: Subjects between 6 and 18 years old were evaluated in this phase 1, open-label, single-dose, prospective study using 10 mg/kg (up to 600 mg). Non-compartmental analysis and population-based PK analyses with Monte Carlo simulation (for doses 8-20 mg/kg every 8 h, infused over 1-4 h) were conducted...
September 14, 2017: Pediatric Pulmonology
https://www.readbyqxmd.com/read/28906458/combination-of-hypertension-along-with-a-high-fat-and-cholesterol-diet-induces-severe-hepatic-inflammation-in-rats-via-a-signaling-network-comprising-nf-%C3%AE%C2%BAb-mapk-and-nrf2-pathways
#7
Yuan Yuan, Hisao Naito, Xiaofang Jia, Kazuya Kitamori, Tamie Nakajima
Populations with essential hypertension have a high risk of nonalcoholic steatohepatitis (NASH). In this study, we investigated the mechanism that underlies the progression of hypertension-associated NASH by comparing differences in the development of high fat and cholesterol (HFC) diet-induced NASH among three strains of rats, i.e., two hypertensive strains comprising spontaneously hypertensive rats and the stroke-prone spontaneously hypertensive 5/Dmcr, and the original Wistar Kyoto rats as the normotensive control...
September 14, 2017: Nutrients
https://www.readbyqxmd.com/read/28901495/biochanin-a-induces-apoptosis-and-suppresses-migration-in-fadu-human-pharynx-squamous-carcinoma-cells
#8
In-A Cho, Sang-Joun You, Kyeong-Rok Kang, Su-Gwan Kim, Ji-Su Oh, Jae-Seek You, Gyeong-Je Lee, Yo-Seob Seo, Do Kyung Kim, Chun Sung Kim, Sook-Young Lee, Jae-Sung Kim
The aim of the present study was to investigate biochanin-A-induced anticancer effects and their cellular signaling pathway in FaDu pharyngeal squamous carcinoma cells. Biochanin-A induced cell death through increased cytotoxicity of FaDu cells in a dose- and time-dependent manner. The number of cells with nucleus condensation and the apoptotic population were increased in the FaDu cells stimulated with biochanin-A for 24 h. Furthermore, extrinsic apoptotic factors such as FasL and their downstream target caspase-8 were increased and activated in the FaDu cells treated with biochanin-A in a dose-dependent manner...
September 13, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28893774/external-evaluation-of-two-fluconazole-infant-population-pharmacokinetic-models
#9
Michael F Hwang, Ryan J Beechinor, Kelly C Wade, Daniel K Benjamin, P Brian Smith, Christoph P Hornik, Edmund V Capparelli, Shahnaz Duara, Kathleen A Kennedy, Michael Cohen-Wolkowiez, Daniel Gonzalez
Fluconazole is an antifungal agent used for the treatment of invasive candidiasis, a leading cause of morbidity and mortality in premature infants. Population pharmacokinetics (PK) models of fluconazole in infants have been previously published by Wade et al. and Momper et al. Here we report the results of the first external evaluation of the predictive performance of both models. We used patient level data from both studies to externally evaluate both PK models. The predictive performance of each model was evaluated using the model prediction error (PE), mean prediction error (MPE), mean absolute prediction error (MAPE), prediction-corrected visual predictive check (pcVPC), and normalized prediction distribution errors (NPDE)...
September 11, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28891980/sinomenine-hydrochloride-inhibits-human-glioblastoma-cell-growth-through-reactive-oxygen-species-generation-and-autophagy-lysosome-pathway-activation-an-in-vitro-and-in-vivo-study
#10
Yumao Jiang, Yue Jiao, Zhiguo Wang, Tao Li, Yang Liu, Yujuan Li, Xiaoliang Zhao, Danqiao Wang
Glioblastoma is the most common malignant primary brain tumor, and it is one of the causes of cancer fatality in both adult and pediatric populations. Patients with glioblastoma require chemotherapy after surgical resection and radiotherapy. Therefore, chemotherapy constitutes a viable approach for the eradication of glioblastoma cells. In this study, the anti-tumor activity of sinomenine hydrochloride (SH) was evaluated in U87 and SF767 cells in vitro and in vivo. The results showed that SH potently inhibited U87 and SF767 cell viability and did not cause caspase-dependent cell death, as demonstrated by the absence of significant early apoptosis and caspase-3 cleavage...
September 11, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28888484/prediction-of-human-efficacious-antidepressant-doses-using-the-mouse-forced-swim-test
#11
Eunice Yuen, Steven Swanson, Jeffrey M Witkin
The forced swim test (FST) is a commonly used preclinical animal behavioural model for prediction of antidepressant activity in humans. While the FST may qualitatively predict efficacy, less is known about the quantitative translation of FST data to human efficacious doses. Assessing quantitative translation allows better predictions of human efficacious doses and a higher chance of success in the drug development process. Dose-response and time-course FST experiments were carried out on mice using four marketed antidepressants (citalopram, desipramine, bupropion, desvenlafaxine) in addition to ketamine, all with varying mechanisms of action...
September 6, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28884840/hydroxycarbamide-in-children-with-sickle-cell-anemia-after-first-dose-vs-chronic-therapy-pharmacokinetics-and-predictive-models-for-drug-exposure
#12
Jeremie H Estepp, Paweł Wiczling, Joseph Moen, Guolian Kang, Joana Marie Mack, Robert Liem, Julie A Panepinto, Uttam Garg, Gregory Kearns, Kathleen A Neville
AIMS: The purpose of this work was to (1) compare pharmacokinetic (PK) parameters for hydroxycarbamide in children receiving their first dose (HCnew ) versus those receiving chronic therapy (HCchronic ), (2) assess the external validity of a published PK dosing strategy, and (3) explore the accuracy of dosing strategies based on a limited number of HC measurements. METHODS: Utilizing data from two prospective, multicenter trials of hydroxycarbamide (Pharmacokinetics of Liquid Hydroxyurea in Pediatric Patients with Sickle Cell Anemia; NCT01506544 and Single-Dose (SD) and Steady-State (SS) Pharmacokinetics of Hydroxyurea in Children and Adolescents with Sickle Cell Disease), plasma drug concentration versus time profiles were evaluated with a model independent approach in the HCnew and HCchronic groups...
September 8, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28884437/extrapolation-of-a-brivaracetam-exposure-response-model-from-adults-to-children-with-focal-seizures
#13
Rik Schoemaker, Janet R Wade, Armel Stockis
INTRODUCTION: Prediction of brivaracetam effects in children was obtained by scaling an existing adult pharmacokinetic/pharmacodynamic (PK/PD) model for brivaracetam to children, using an existing population PK model for brivaracetam in children. The scaling was supported by estimating the change from adults to children in the concentration-effect relationship parameters for levetiracetam, a compound interacting with the same target protein (synaptic vesicle protein SV2A). METHODS: The existing adult PK/PD model for brivaracetam was applied to a combined adult-pediatric dataset of levetiracetam...
September 7, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28875397/boceprevir-and-antiretroviral-pharmacokinetic-interactions-in-hiv-hcv-co-infected-persons-aids-clinical-trials-group-study-a5309s
#14
Jennifer J Kiser, Darlene Lu, Susan L Rosenkranz, Gene D Morse, Robin DiFrancesco, Kenneth E Sherman, Adeel A Butt
OBJECTIVE: The objective of this study was to determine the magnitude of drug interactions between the hepatitis C virus (HCV) protease inhibitor boceprevir (BOC) and antiretroviral (ARV) agents in persons with HIV/HCV co-infection. METHODS: Participants taking two nucleos(t)ide analogs with either efavirenz, raltegravir, or ritonavir-boosted atazanavir, darunavir, or lopinavir underwent intensive pharmacokinetic (PK) sampling for ARV 2 weeks before (week 2) and 2 weeks after initiating BOC (week 6) and for BOC at week 6...
September 5, 2017: Drugs in R&D
https://www.readbyqxmd.com/read/28872908/pharmacokinetic-profile-of-edaravone-a-comparison-between-japanese-and-caucasian-populations
#15
Yoshinobu Nakamaru, Shuji Kinoshita, Atsuhiro Kawaguchi, Koji Takei, Joseph Palumbo, Masayuki Suzuki
BACKGROUND: Amyotrophic lateral sclerosis (ALS) affects persons of all races, and there continues to be a need for effective therapies to treat the disease. OBJECTIVE: To compare the pharmacokinetics (PK) of edaravone between Japanese and Caucasian populations. METHODS: Data from five PK studies among Japanese and Caucasian healthy volunteers were pooled and evaluated. In population PK (PPK) modelling, compartment models and other models with linear elimination were evaluated for appropriateness...
October 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28869834/pkr-activation-causes-inflammation-and-mmp-13-secretion-in-human-degenerated-articular-chondrocytes
#16
Ching-Hou Ma, Chin-Hsien Wu, I-Ming Jou, Yuan-Kun Tu, Ching-Hsia Hung, Pei-Ling Hsieh, Kun-Ling Tsai
Osteoarthritis (OA) is a degenerative joint disease affecting a large population of people. Although the elevated expression of PKR (double stranded RNA-dependent protein kinase) and MMP-13 (collagenase-3) have been indicated to play pivotal roles in the pathogenesis of OA, the exact mechanism underlying the regulation of MMP-13 by PKR following inflammatory stimulation was relatively unknown. The purpose of this study was to determine the signaling pathway involved in the PKR-mediated induction of MMP-13 after TNF-α-stimulation...
August 24, 2017: Redox Biology
https://www.readbyqxmd.com/read/28869786/population-pharmacokinetic-pharmacodynamic-modelling-of-auditory-evoked-event-related-potentials-with-lorazepam
#17
Aurélie Lombard, Claire Brittain, Graham Wishart, Stephen Lowe, Andrew McCarthy, William Landschulz, Georg Dorffner, Peter Anderer, Eunice Yuen
Event-Related Potentials (ERPs) are commonly used in Neuroscience research, particularly the P3 waveform because it is associated with cognitive brain functions and is easily elicited by auditory or sensory inputs. ERPs are affected by drugs such as lorazepam, which increase the latency and decrease the amplitude of the P3 wave. In this study, auditory-evoked ERPs were generated in 13 older healthy volunteers using an oddball tone paradigm, after administration of single 0.5 and 2mg doses of lorazepam. Population pharmacokinetics (PK)/ pharmacodynamics (PD) models were developed using non-linear mixed effects methods in order to assess the effect of lorazepam on the latency and amplitude of the P3 waveforms...
September 4, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28869666/comprehensive-guidance-for-antibiotic-dosing-in-obese-adults
#18
Lina Meng, Emily Mui, Marisa K Holubar, Stan C Deresinski
BACKGROUND: Physiologic alterations seen in obesity commonly impact the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics and may result in suboptimal dosing in this expanding but understudied population. Much of the published clinical and PK evidence to date consists of small patient populations and are retrospective with, not infrequently, heterogenous results that, in some cases, are contradictory. In the last 10 years, additional antimicrobial PK/PD and clinical data encompassing prolonged infusion strategies and examination of critically ill populations has emerged to inform antimicrobial dosing in obesity...
September 4, 2017: Pharmacotherapy
https://www.readbyqxmd.com/read/28865048/assessing-the-combined-toxicity-of-conventional-and-newer-insecticides-on-the-cotton-mealybug-phenacoccus-solenopsis
#19
Bushra Saddiq, Masood Ejaz, Sarfraz Ali Shad, Muhammad Aslam
Reduced susceptibility to insecticides often results in failure of insect pest control and repetitive use of broad-spectrum insecticides, which could have detrimental effects on beneficial arthropods and surrounding agro-ecosystems. The cotton mealybug, Phenacoccus solenopsis Tinsley is a pest of worldwide importance that can be effectively controlled using a number of insecticides. This insect has developed resistance due to injudicious use and repeated exposure to insecticides throughout the year. The aim of the present study was to investigate the toxicity of the insecticides chlorpyrifos, deltamethrin, spinosad, emamectin benzoate and indoxacarb tested either singly or in combination on laboratory susceptible (Lab-PK) and field population (Field Pop) of P...
September 1, 2017: Ecotoxicology
https://www.readbyqxmd.com/read/28864105/morphine-and-metabolites-plasma-levels-after-administration-of-sustained-release-morphine-in-roux-en-y-gastric-bypass-subjects-versus-matched-control-subjects
#20
Lorry Hachon, Rafael Reis, Laurence Labat, Christine Poitou, Aude Jacob, Xavier Declèves, Celia Lloret-Linares
BACKGROUND: Better knowledge of opioid pharmacology after Roux-en-Y gastric bypass (RYGB) is required for optimizing their use in this growing population. OBJECTIVE: The aim of this case-controlled pharmacokinetic (PK) study was to compare morphine and its glucuronidated metabolites (morphine-3-glucuronide and morphine-6-glucuronide) plasma PKs between patients with RYGB and their controls. SETTINGS: University hospital, Lariboisière Hospital, Paris...
August 3, 2017: Surgery for Obesity and related Diseases: Official Journal of the American Society for Bariatric Surgery
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